In silico investigation of hepatitis c virus: a novel perspective into targeted viral inhibition of NS3 helicase, NS 3/4a protease and NS5b RNA dependent RNA polymerase.
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2019
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Abstract
Hepatitis C Virus (HCV) is an escalating global healthcare and economic burden that requires extensive
intervention to alleviate its control. Over the years, drug design efforts have produced many anti-HCV
drugs; however, due to drug resistance brought on by numerous genetic variations of the virus and lack
of specificity and stability, current drugs are rendered ineffective. The situation has been further
intensified by the absence of a viable vaccine. For these reasons, continuous HCV research is imperative
for the design and development of promising inhibitors that address the challenges faced by present
antiviral therapies. Moreover, exposure of previously neglected viral protein targets can offer another
potentially valuable therapeutic route in drug design research.
Structure-based drug design approaches accentuate the development of small inhibitor molecules that
interact with therapeutic targets through non-covalent interactions. The unexpected discovery of
covalent inhibitors and their distinctive nature of instigating complete and irreversible inhibition of
targets have shifted attention away from the use of non-covalent drugs in antiviral treatment. This has
led to significant progress in understanding covalent inhibition regarding their underlying mechanism
of action and in the design of novel covalent inhibitors that work against biological targets. However,
due to difficulties arising in its application and resultant safety, the pharmaceutical industry were
reluctant to pursue this strategy. With the use of rational drug design, a novel strategy was then proposed
known as selective covalent inhibition. Due to the lack of competent protocols and information, little is
known regarding selective covalent inhibition
This study investigates three biological HCV targets, NS3 protease, RNA helicase and NS5B RNAdependent RNA polymerase. With constantly evolving viruses like HCV, computational methods
including molecular modelling and docking, virtual screening and molecular dynamic simulations have
allowed chemists to screen millions of compounds to filter out potential lead drugs. These in silico
approaches have allowed Computer-Aided Drug Design as a cost-effective strategy to accelerate the
process of drug discovery.
The above techniques, with numerous other computational tools were employed in this study to fill the
gap in HCV drug research by providing insights into the structural and dynamic changes that describe
the mechanism of selective covalent inhibition and pharmacophoric features that lead to unearthing of
potential small inhibitor molecules against Hepatitis C.
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The first study (Chapter 4) provides a comprehensive review on HCV NS3/4A protein, current therapies
and covalent inhibition as well as introduces a technical guideline that provides a systematic approach
for the design and development of potent, selective HCV inhibitors.
The second study (Chapter 5) provides a comprehensive understanding concerning the implications of
selective covalent inhibition on the activity of HCV NS5B RNA-dependent RNA polymerase, with
respect to key components required for viral replication, when bound to a target-specific small inhibitor
molecule.
The third study (Chapter 6) is preliminary investigation that uses Pharmacophore-based virtual
screening as an efficient tool for the discovery of improved potential HCV NS3 helicase inhibitors. The
pharmacophoric features were created based on the highly contributing amino acid residues that bind
with highest affinity to the weak inhibitor, quercetin. These residues were identified based on free
energy footprints obtained from molecular dynamic and thermodynamic calculations. Post molecular
dynamic analysis and appropriate drug-likeness properties of the three top-hit compounds revealed that
ZINC02495613 could be a more effective potential HCV helicase inhibitor; however, further validation
steps are still required.
This study offers a comprehensive in silico perspective to fill the gap in rational drug design research
against HCV, thus providing an insight into the mechanism of selective covalent inhibition, uncovering
a previously neglected viral target and identifying possible antiviral drugs. To this end, the work
presented in this report is considered a fundamental platform to advance research toward the design and
development of novel and selective anti-HCV drugs.
Description
Doctoral Degrees (Pharmaceutical Sciences). University of KwaZulu-Natal. Westville, 2019.